Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers
Cell-penetrating peptides (CPPs) are widely used for the intracellular delivery of a variety of cargo molecules, including small molecules, peptides, nucleic acids, and proteins. Many cationic and amphiphilic CPPs have been developed; however, there have been few reports regarding hydrophobic CPPs....
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/14/11768 |
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| author | Keisuke Tsuchiya Kanako Horikoshi Minami Fujita Motoharu Hirano Maho Miyamoto Hidetomo Yokoo Yosuke Demizu |
| author_facet | Keisuke Tsuchiya Kanako Horikoshi Minami Fujita Motoharu Hirano Maho Miyamoto Hidetomo Yokoo Yosuke Demizu |
| author_sort | Keisuke Tsuchiya |
| collection | DOAJ |
| description | Cell-penetrating peptides (CPPs) are widely used for the intracellular delivery of a variety of cargo molecules, including small molecules, peptides, nucleic acids, and proteins. Many cationic and amphiphilic CPPs have been developed; however, there have been few reports regarding hydrophobic CPPs. Herein, we have developed stapled hydrophobic CPPs based on the hydrophobic CPP, TP10, by introducing an aliphatic carbon side chain on the hydrophobic face of TP10. This side chain maintained the hydrophobicity of TP10 and enhanced the helicity and cell penetrating efficiency. We evaluated the preferred secondary structures, and the ability to deliver 5(6)-carboxyfluorescein (CF) as a model small molecule and plasmid DNA (pDNA) as a model nucleotide. The stapled peptide <b>F-3</b> with CF, in which the stapling structure was introduced at Gly residues, formed a stable α-helical structure and the highest cell-membrane permeability via an endocytosis process. Meanwhile, peptide <b>F-4</b> demonstrated remarkable stability when forming a complex with pDNA, making it the optimal choice for the efficient intracellular delivery of pDNA. The results showed that stapled hydrophobic CPPs were able to deliver small molecules and pDNA into cells, and that different stapling positions in hydrophobic CPPs can control the efficiency of the cargo delivery. |
| first_indexed | 2024-03-11T00:59:52Z |
| format | Article |
| id | doaj.art-93b752e4577046818092b656962bd457 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:59:52Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-93b752e4577046818092b656962bd4572023-11-18T19:44:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141176810.3390/ijms241411768Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug CarriersKeisuke Tsuchiya0Kanako Horikoshi1Minami Fujita2Motoharu Hirano3Maho Miyamoto4Hidetomo Yokoo5Yosuke Demizu6Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi 210-9501, JapanCell-penetrating peptides (CPPs) are widely used for the intracellular delivery of a variety of cargo molecules, including small molecules, peptides, nucleic acids, and proteins. Many cationic and amphiphilic CPPs have been developed; however, there have been few reports regarding hydrophobic CPPs. Herein, we have developed stapled hydrophobic CPPs based on the hydrophobic CPP, TP10, by introducing an aliphatic carbon side chain on the hydrophobic face of TP10. This side chain maintained the hydrophobicity of TP10 and enhanced the helicity and cell penetrating efficiency. We evaluated the preferred secondary structures, and the ability to deliver 5(6)-carboxyfluorescein (CF) as a model small molecule and plasmid DNA (pDNA) as a model nucleotide. The stapled peptide <b>F-3</b> with CF, in which the stapling structure was introduced at Gly residues, formed a stable α-helical structure and the highest cell-membrane permeability via an endocytosis process. Meanwhile, peptide <b>F-4</b> demonstrated remarkable stability when forming a complex with pDNA, making it the optimal choice for the efficient intracellular delivery of pDNA. The results showed that stapled hydrophobic CPPs were able to deliver small molecules and pDNA into cells, and that different stapling positions in hydrophobic CPPs can control the efficiency of the cargo delivery.https://www.mdpi.com/1422-0067/24/14/11768cell-penetrating peptidestapled peptidehydrophobic peptidehelical structureplasmid DNA delivery |
| spellingShingle | Keisuke Tsuchiya Kanako Horikoshi Minami Fujita Motoharu Hirano Maho Miyamoto Hidetomo Yokoo Yosuke Demizu Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers International Journal of Molecular Sciences cell-penetrating peptide stapled peptide hydrophobic peptide helical structure plasmid DNA delivery |
| title | Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers |
| title_full | Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers |
| title_fullStr | Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers |
| title_full_unstemmed | Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers |
| title_short | Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers |
| title_sort | development of hydrophobic cell penetrating stapled peptides as drug carriers |
| topic | cell-penetrating peptide stapled peptide hydrophobic peptide helical structure plasmid DNA delivery |
| url | https://www.mdpi.com/1422-0067/24/14/11768 |
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